ABSTRACT
We have already reported the modification on the piperazine and phenyl rings of JNJ4796, a small-molecule fuse inhibitor targeting hemagglutinin (HA). In this study, we described the structure-activity relationship of the benzoxazole and tetrazole rings of JNJ4796. Many derivatives demonstrated good in vitro activity against IAV H1N1and Oseltamivir-resistant IAV H1N1 stains. Although compounds (R)-1e and (R)-1h exhibited excellent in vitro activity, high drug exposure level and low hERG inhibition, they displayed low oral efficacy. Excitedly, (R)-1a, a representative identified in our previous study, was found to show potent in vivo anti-IAV activity with the survival rates of 100%, 100% and 70% at 15, 5 and 1.67 mg/kg, respectively, comparable to JNJ4796. Currently, we are exploring different ways to ease its gastrointestinal response.
Subject(s)
Antiviral Agents , Benzoxazoles , Influenza A Virus, H1N1 Subtype , Piperazines , Tetrazoles , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Piperazines/chemistry , Piperazines/pharmacology , Tetrazoles/chemistry , Tetrazoles/pharmacology , Structure-Activity Relationship , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , HumansABSTRACT
Influenza virus is a virus causing upper respiratory tract infection disease with high morbidity and mortality. China is considered as an area with high rate of influenza morbidity. Prevention and treatment of influenza currently rely on vaccines and antiviral agents in the world. In addition, traditional Chinese medicines also have been used in clinical for influenza therapy. In vitro anti-influenza virus activities of 10 traditional Chinese medicines were studied by cytopathic effect (CPE). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Guangdong Luohu/219/2006 (H1N1); Yinhuang oral liquid had strong antiviral activity against influenza virus A/Hanfang/359/95 and A/Yuefang/243/72 (H3N2). Qingkailing oral liquid (factory G) had strong antiviral activity against influenza virus A/Jifang/15/90 (H3N2). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Jifang/15/90, A/Yuefang/243/72 (H3N2) and virus B.
Subject(s)
Antiviral Agents/pharmacology , Cytopathogenic Effect, Viral/drug effects , Drugs, Chinese Herbal/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H3N2 Subtype/drug effects , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line , Chlorogenic Acid/administration & dosage , Chlorogenic Acid/pharmacology , Dogs , Drugs, Chinese Herbal/administration & dosage , Flavonoids/administration & dosage , Flavonoids/pharmacology , Indoles/administration & dosage , Indoles/pharmacology , Influenza B virus/drug effects , Iridoids/administration & dosage , Iridoids/pharmacologyABSTRACT
Ribavirin is a broad-spectrum inhibitor against several unrelated DNA or RNA viruses in vitro and in vivo. In this paper the in vitro and in vivo study of anti-influenza virus activity of ribavirin (RBV) injection had been reported. The in vitro antiviral activity of ribavirin injection against influenza virus A and B was studied by CPE. The in vivo protective action of ribavirin injection against influenza A/FM/1/47(H1N1) mouse adapted strain infected mouse was studied with mouse model. The results showed ribavirin injection has strong inhibitory activity against 7 virus strains tested in vitro. Ribavirin injection could significantly increase virus infected mouse survival rate and survival days and improve lung pathogen and lung index.
